1. Field of the disclosure
The field of art of this disclosure generally concerns chemicals designed to act as peripheral antinociceptive drugs. By “peripheral”, I mean that the target of the drug action is located outside the central nervous system, that is, outside of the brain and spinal cord. By “antinociceptive”, I mean that the drug suppresses the perception of noxious stimuli. The compounds described are aryl-substituted derivatives of cycloalkyl and branched chain alkyl carboxamides and carboxylic acids useful in treating clinical disorders such as itch, pain, and sensory discomforts from breathing disorders, lower urinary tract disorders, bowel dysfunction and as insect repellents.
2. Description of Related Art
There are currently two major classes of drugs that act peripherally to attenuate transmission of nociceptive signals to the central nervous system. One class of drugs are the local anesthetics, such as procaine and lidocaine, which act on peripheral nerve fibers to inhibit conduction of noxious signals towards the central nervous system. Another class of drugs are agents like aspirin and ibuprofen which inhibit the synthesis of certain prostaglandins. These prostaglandins when released by tissues during injury or inflammation lower the threshold of firing of sensory nerve fibers that respond to noxious stimuli. A third group of drugs, the narcotic analgesics, are effective in the suppression of pain, but they act within the brain and the spinal cord.
Local anesthetic compounds are not active orally and must be infiltrated into tissues containing the target nerve fibers. The aspirin/non-steroidal anti-inflammatory compounds (NSAID and thenarcotic analgesics ) are effective drugs but the NSAIDs may produce gastric ulceration and kidney failure and the narcotics have side-effects such as respiratory depression, tolerance and dependence. The NSAIDs reduce inflammatory pain, but are not effective against neuropathic or visceral pain. The treatment of neuropathic pain is especially complex, with empirical use of agents such as amitriptyline, clonazepam, clonidine, carbamazepine and gabapentin.
Pain, defined by Sir Charles Sherrington as “the psychic adjunct of an imperative protective reflex”, is activated by increased discharge of small-diameter sensory fibers. Anatomically, these fibers are called unmyclinated C fibers and thinly myelinated Aδ fibers. Functionally, these fibers are also called polymodal and may contain in one group neuropeptides such as calcitonin-gene related peptide and substance P, or in another group contain phosphatases and binding sites for isolectin B4. These sensory fibers also contain various receptors, including the transient potential receptor (TRP) potential family of receptors that code for thermosensation and pain. Pain is categorized as nociceptive or neuropathic, the first caused by tissue injury and the latter caused by direct damage to the nerve fiber. There are many conditions that produce pain, for example, acute pain after tissue trauma, chronic pain from osteoarthritis, cancer pain, and neuropathic pain, for example, associated with end-stage renal diseases and with diabetes mellitus. Other related sensory disorders arising from polymodal neuronal elements are pruritus, for example from uremia, cholestasis, various forms of dermatitis, polycythemia vera, hyperthyroidism, lymphoma, and human immunodeficiency (HIV) virus infections; and sensations from the nasal membranes, for example, the urge to sneeze; and sensations from the upper airways, for example, the urge to cough.
Another form of sensory fiber disorder is visceral hyper-sensitivity or hyper-reflexia. Urinary incontinence (UI) is defined as the involuntary loss of urine that can be demonstrated objectively and which constitutes a social or hygienic problem. UI occurs when the pressure within the bladder exceeds that within the urethra during the filling phase. Overactive bladder (OA) and urge incontinence is a type of UI that is associated with a strong desire to urinate and correlates with an overactive detrusor muscle. Urge incontinence is usually recognized by the abrupt sensation that urination is imminent and can occur even when the bladder is virtually empty.
It is estimated that OA affects more 17 million Americans, making it more prevalent than, for example, asthma, osteoporosis, diabetes mellitus or Alzheimer's disease. OA with urge incontinence is a problem in older men with bladder irritation from benign prostate hypertrophy (BPH), a condition which obstructs urine passage. In women, stress incontinence, a sub-category of UI, arises as a defect in the urethral closure mechanism caused, for example, by physical damage to muscle and nerves on the pelvic floor, bladder neck, or urethra during childbirth. Sufferers of stress incontinence have leak of small volumes of urine after actions such as laughing, coughing, sneezing, lifting, jumping and running, all of which produce abrupt increases in intra-abdominal pressure. Stress incontinence is estimated to affect approximately 25% of women with urinary incontinence and surgery is the most effective treatment with a cure rate of 75 to 85%. Other conditions that may produce OA are lower urinary tract infections and chronic inflammation, such interstitial cystitis.
Pharmacotherapy is currently the principal treatment for OA. Selective antimuscarinic drugs, such as oxybutynin and tolterodine, designed to inhibit smooth muscle contraction in the detusor, are administered to reduce the frequency of uncontrolled contractions and of voiding. These drugs are claimed to be effective in about 60% of the patient population, but longterm compliance is low, possibly because of side-effects of these drugs such as dry mouth. Another agent is phenazopyridine, an azo dye that is thought to act as an urinary anesthetic. This compound, however, can cause methemoglobinemia, turns the urine to a yellow-orange to red color, and produces adenocarcinomas (cancers) in experimental animals. Intravesical instillation of vanilloid agonists, such as capsaicin and resinerferatoxin, is also used as an experimental form of treating OA, but the chemicals are difficult to administer and causes severe irritation as a side-effect.
Like the bladder, the gut is a complex organ with its own enteric nervous system. The simplified “brain” of the gut has about 100 million neurons. The efferent nerves regulate secretion by intestinal glands and control peristalsis. Sensory afferent nerves (Aδ and C) fibers located in the gut respond to thermal and nociceptive signals. The lining of the gut has high metabolic activity and a turnover rate of about 5 days, that is, within a period of 5 days, the entire lining is shed and renewed. This is a turnover of about ¼ pounds of cells per day. Injury to the intestinal mucosa from exposure to chemical agents such as anticancer drugs, from inflammatory responses, and from autoimmune diseases, from infections, or from physical injuries such as radiation or trauma, disrupt the enteric nervous system and contribute to symptoms and signs such as pain, a sense of distension, changes in the frequency of bowel movements, intra-luminal bleeding, and flatulence.
Irritable bowel syndrome (IBS) is a common disorder characterized by abdominal pain in the setting of altered perception of viscerosensory stimuli. This so-called visceral hyperalgesia (or hypersensitivity) occurs in the absence of detectable organic disease in the peripheral organs and may cause normal or physiologic contractions to be perceived as painful. Although the pathogenesis of IBS remains speculative and is probably multifactorial, a prevailing paradigm is that transient noxious events lead to long-lasting sensitization of the neural pain circuit, despite complete resolution of the initiating event. A similar situation exists in inflammatory bowel disease (IBD), the two principal conditions being Crohn's disease and ulcerative colitis. In IBD there is clear evidence of organ histopathology and the symptoms and signs of pain and discomfort are present to a greater extent, sometimes requiring surgical removal of the lower bowel. Currently pharmacological treatment of IBS includes tegaserod (Zelnorm®), a selective 5-hydroxytrptamine receptor agonist, designed to overcome the constipation-predominant type of IBS. For IBD treatment, a prodrug, sulfaslazine, or 5-aminosalicylic acid is used. These drugs modulate the IBD processes in the gut.
Proctitis is inflammation of the lining of the rectum. Proctitis can be short term (acute) or long term (chronic). Proctitis has many causes. It may be a side effect of autoimmune diseases of the lower bowel, such as ulcerative colitis and Crohn's disease. Sexually transmitted diseases may cause proctitis. Proctitis is frequently a side-effect of radiation used to treat prostate cancer or cancer of the female organs. The rectum resides just behind the prostate in the male and the vagina and uterus in the female, so when these organs are irradiated, the bowel wall is injured. Radiation proctitis is manifested as the new growth of many tiny blood vessels on the epithelial surface of the rectum. These blood vessels are fragile and bleed with minimal trauma, resulting in blood in the stool. If the bleeding is severe, anemia or a low red cell blood count can occur. Other causes of proctitis include traumatic rectal injury, allergies, and malfunction of the nerves in the rectum. Patients infected with human immunodeficiency virus or receiving immunosuppressive drugs are especially susceptible to infectious agents attacking the lower gut lining and surrounding tissues.
The most common manifestation of proctitis is a frequent or continuous sensation of an urge to have a bowel movement. This distressing but ineffectual urge to empty the rectum is called tenesmus. Other symptoms include constipation, a feeling of rectal fillness, left-sided abdominal pain, passage of mucus through the rectum, rectal bleeding, and anorectal pain. Proctitis because it leads to bleeding, some incontinence, and inflammation will produce subjective discomfort, pain, and itch in the entire anorectal area.
The surfaces of the upper airways (nose, pharynx, bronchi and bronchioles) are densely innervated and any inflammation or altered airflow quickly generates sensations of itch, irritation, obstruction, choking, air hunger, suffocation and subjective discomfort. The sensory nerves that mediate the sensations of breathing disorders are also the target of the drugs of this invention; the therapeutic goal being to provide refreshed breathing, less sneezing and coughing, decreased inspiratory effort, and relief of dyspnea.
I have previously described the use of certain compounds to treat itch or pain. Thus, U.S. patent application, publication No. 2003/0207851, published Nov. 6, 2003, titled “Therapeutic 1,2,3,6-tetrahydropyrimidine-2-one compositions and methods therewith” describes a therapeutic composition that comprises a 1-R1-phenyl, 4R2-phenyl substituted 1,2,3,6-tetrahydropyrimidine-2-one cold receptor agonist in a therapeutically effective amount. A particularly preferred cold receptor agonist embodiment is called “icilin” and a particularly preferred composition has icilin dispersed as an emulsion in a dermatologically acceptable vehicle. Icilin, formulated and administered as a liniment, and preferably in combination with one or more pharmaceutically active drugs, offers improved therapeutic benefit for the treatment of pruritus.
Watson et al. N-Substituted Paramenthane Carboxamides, U.S. Pat. No. 4,193,936, Mar. 18, 1980 and Rowsell et al., Alicyclic Amides Having a Physiological Cooling Effect, U.S. Pat. No. 4,318,900, Mar. 9, 1982, disclosed compounds with physiological cooling effects. Various uses of the Watson et al. and Rowsell et al. compounds are noted in several subsequent patents: Cherukuri et al., U.S. Pat. No. 5,009,893, Apr. 23, 1991; Upson et al. U.S. Pat. No. 5,244,670, Sep. 14, 1993; Luo, U.S. Pat. No. 5,698,181, Dec. 16, 1997; and Zanone et al., U.S. Pat. No. 6,497,859, Dec. 24, 2002. These compounds are also claimed for use as an insect repellent in Gautschi et al., WO 02/15692 A1, Feb. 28, 2002.